Alarming increases in the incidence, morbidity and mortality from allergic asthma in children have been documented in the US over the last decade. The underlying cause(s) of this increase are unknown. Recent epidemiological studies have documented a positive association between levels of urban airborne particulate matter (PM) and exacerbations of asthma, although a causal relationship has not been established. Importantly, preliminary studies conducted in the Center have provided compelling evidence that reductions in ambient airborne PM in homes of asthmatic children is associated with significant improvement in asthma morbidity. However, the exact mechanisms by which indoor PM exposure may exacerbate or induce asthma remain unknown. Our preliminary data suggest that exposure of mice to outdoor sources of PM alone in the absence of allergen exposure induces many features of the allergic response (Airway hyperresponsiveness, airway inflammation, Th2 cytokine production). Furthermore, our data suggest that the induction of airway hyperresponsiveness is mediated via the innate immune system mediator, complement factor 3 (C3). Interestingly, several components of indoor PM (i.e. allergens, outdoor source PM, tobacco smoke) have also been shown to activate the complement pathway. Thus the overall goal of this proposal is to establish a causal relationship between airborne indoor PM exposure and asthma morbidity and to determine the mechanisms by which indoor PM elicits these effects. Thus, we plan to test the hypothesis that individual components of indoor PM exposure serve to enhance adaptive immune responses to allergens by inducing the release or activation of C3. The specific aims of this proposal are: First, to determine whether exposure to airborne indoor PM collected from homes in urban Baltimore induces the onset or worsening of allergic asthma. Specifically, we will compare the biologic effects of PM collected in homes of children with mild and severe asthma stratified for the presence of smokers in the home. Secondly, to determine whether a gene-environment interaction is important in responses to indoor PM, we will determine the biological effects of indoor PM exposure in non-allergic strains of mice. Thirdly, we will determine the role of C3 in mediating airborne indoor PM-induced inflammation and/or exacerbations of allergic asthmatic symptoms by comparing these responses in C3 deficient and wildtype mice. These studies will provide insight into the immunopathogenic mechanisms involved in PM-induced exacerbation of asthma and establish a dose-relationship upon which to base air quality standards to protect the health of susceptible individuals in our society such as asthmatic children living in urban environments.